T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations - 06/09/18
Abstract |
Background |
Mutations in the perforin 1 (PRF1) gene account for up to 58% of familial hemophagocytic lymphohistiocytosis syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinemia and hyperactivation with inflammation in various organs.
Objective |
We sought to determine whether autologous gene-corrected T cells can restore cytotoxic function, reduce disease activity, and prevent hemophagocytic lymphohistiocytosis (HLH) symptoms in in vivo models.
Methods |
We developed a gammaretroviral vector to transduce murine CD8 T cells in the Prf−/− mouse model. To verify functional correction of Prf−/− CD8 T cells in vivo, we used a lymphocytic choriomeningitis virus (LCMV) epitope–transfected murine lung carcinoma cell tumor model. Furthermore, we challenged gene-corrected and uncorrected mice with LCMV. One patient sample was transduced with a PRF1-encoding lentiviral vector to study restoration of cytotoxicity in human cells.
Results |
We demonstrated efficient engraftment and functional reconstitution of cytotoxicity after intravenous administration of gene-corrected Prf−/− CD8 T cells into Prf−/− mice. In the tumor model infusion of Prf−/− gene–corrected CD8 T cells eliminated the tumor as efficiently as transplantation of wild-type CD8 T cells. Similarly, mice reconstituted with gene-corrected Prf−/− CD8 T cells displayed complete protection from the HLH phenotype after infection with LCMV. Patients' cells showed correction of cytotoxicity in human CD8 T cells after transduction.
Conclusion |
These data demonstrate the potential application of T-cell gene therapy in reconstituting cytotoxic function and protection against HLH in the setting of perforin deficiency.
Le texte complet de cet article est disponible en PDF.Key words : Gene therapy, hemophagocytic lymphohistiocytosis, perforin deficiency, T cells
Abbreviations used : FHL, GFP, HLH, HSCT, IRES, LCMV, NK, PRF1, PS, TCM, TEM, WT
Plan
| Supported by grants from the German Research Foundation–Deutsche Forschungsgemeinschaft (grant no. GH 154/1-1 to S.G. and SFB1160, TP1 to S.E.), the Histiocytosis Research Trust and UCL Therapeutics Innovation Fund (to M.C.), the Wellcome Trust (to A.J.T.), the DAAD and the German Federal Ministry of Research and Education (to A.S.), the European Commission's 7th Framework Program Contract 261387 (CELL-PID), and grant MR/L012855/1 from the Medical Research Council. The authors would like to acknowledge the support of Great Ormond Street Hospital Children's Charity (to H.B.G.). This study was also supported by the National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital and University College London. |
|
| Disclosure of potential conflict of interest: S. Ghosh received a grant from the DFG (German Research Foundation) for this work. M. Carmo's institution received grants from the Medical Research Council (MRC) and the Histiocytosis Research Trust for this work and is employed by GlaxoSmithKline. M. Calero-Garcia is employed by GlaxoSmithKline. A. Schambach's institution received a grant from SCIDNET and CELLPID for this work and is employed by Hannover Medical School. S. Ehl's institution received a grant from BMBF and DFG for this work and from UCB for other works, and he personally received consultancy fees from UCB. A. J. Thrasher received board membership and consultancy fees from Orchard Therapeutics, Torus, and Rocket Pharmaceuticals and holds stock options from Orchard Therapeutics and Torus. H. B. Gaspar received board membership, consultancy fees, and stock options from Orchard Therapeutics. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 3
P. 904 - septembre 2018 Retour au numéro
Article précédent
- The ? and ?2? auxiliary subunits of voltage-gated calcium channel 1 (Cav1) are required for TH2 lymphocyte function and acute allergic airway inflammation
- Nicolas Rosa, Emily Triffaux, Virginie Robert, Marion Mars, Martin Klein, Gregory Bouchaud, Astrid Canivet, Antoine Magnan, Jean-Charles Guéry, Lucette Pelletier, Magali Savignac
- An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome
- Aleksandra Gil-Krzewska, Mezida B. Saeed, Anna Oszmiana, Elizabeth R. Fischer, Kathryn Lagrue, William A. Gahl, Wendy J. Introne, John E. Coligan, Daniel M. Davis, Konrad Krzewski
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?